CN116615178A - 美容四肽、组合物及用途 - Google Patents
美容四肽、组合物及用途 Download PDFInfo
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- CN116615178A CN116615178A CN202180077352.5A CN202180077352A CN116615178A CN 116615178 A CN116615178 A CN 116615178A CN 202180077352 A CN202180077352 A CN 202180077352A CN 116615178 A CN116615178 A CN 116615178A
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Abstract
四肽具有通式X‑LLAN‑Z，其中在N末端的X选自H、‑CO‑R1、‑SO2‑R1或生物素酰基基团，在C末端的Z选自OH、OR1、NH2、NHR1或NR1R2，并且R1和R2选自烷基、芳基、芳烷基、烷芳基、烷氧基、糖和芳氧基，所述基团具有1至24个碳原子。优选的肽是Pal‑LLAN。这种四肽能够刺激构成真皮细胞外基质的分子(特别是胶原蛋白1和肌原纤蛋白1)的合成，并能够用于美容处理，特别是抗衰老、抗皱纹和细纹，以改善皮肤的机械性能、紧致度/色调/弹性/柔韧性，以增加皮肤密度和体积，用于获得重建效果和/或对抗妊娠纹和皮肤下垂。该肽还适用于刺激毛发生长。
Description
技术领域
本发明涉及新的四肽、包含其的组合物和其在美容中的用途。更具体地涉及适合用于处理哺乳动物、动物或人类的皮肤及其覆盖物(如毛发、睫毛、眉毛、指甲)的四肽。涉及(局部或口服)美容品、卫生和个人护理产品以及皮肤药学产业。
背景技术
肽在体内具有重要的信号传导功能且协调许多生化过程。因此，肽已经变成必不可少的和有前途的活性成分，特别是在美容产业中，其中不断地寻找能够美化皮肤及其覆盖物的新化合物，以改善它们的总体状况。
本发明人对发现对构成真皮细胞外基质(ECM)的分子具有活性的新肽特别感兴趣，所述分子随年龄减少，例如胶原蛋白I和纤连蛋白。
由于成纤维细胞(负责细胞生成的真皮细胞)刺激ECM分子的合成，从而获得美化皮肤和改善其一般状况的结果，特别是在机械性能方面：获得了更致密、饱满的、更紧致、色调更匀称、更柔软和更有弹性的皮肤，肽具有丰盈、饱满以及从而抗皱纹的效果。在肤色缺陷的水平上也获得了结果(肤色更均匀，并且光泽得到改善)。
已经提出了许多能够刺激胶原蛋白I合成的肽或抗衰老肽的混合物，特别是由申请人提出，诸如以商标MATRIXYLTM销售的Pal-KTTKS(SEQ ID N°1)，Pal-GHK，Pal-GQPR(SEQID N°2)，以商标MATRIXYLTM 3000销售的这两种肽的混合物，以商标MATRIXYL synthe'6TM的Pal-KMO2K(MO2对应于二氧化甲硫氨酸)或更近地以商标MATRIXYL MorphomicsTM销售的Pal-K(P)HG(具有嫁接在赖氨酸上的脯氨酸)。在美容品中已经提出了其他肽，因为它们具有刺激弹性蛋白合成的特异性能力，例如由申请人以商标IDEALFTTM销售的Ac-YR-十六烷基酯，或由申请人以商标DERMAXYLTM销售的Pal-VGVAPG(SEQ ID N°3)。
肽序列可以对应于或近似于ECM组成分子的片段。例如，KTTKS肽序列(SEQ ID N°4)对应于胶原蛋白的片段，VGVAPG序列(SEQ ID N°5)对应于弹性蛋白的片段。术语“细胞外基质活化素(matrikines)”用于那些通过模仿刺激细胞活性和相应大分子合成的肽。
发明内容
本发明的目的是提供另一种肽，其可以改善皮肤及其覆盖物的一般状况，并且更具体地，提供对ECM蛋白的合成具有活性的肽。此外，本发明旨在提供足够有效以单独使用或组合使用的肽，所述肽从几个ppm起具有活性，并且以局部组合物、特别是美容品组合物的形式存在。
本发明提供了式1的四肽：
X-LLAN-Z(SEQ ID N°6)
其中：
-在N末端的X选自H、-CO-R1、-SO2-R1或生物素酰基基团；
-在C末端的Z选自OH、OR1、NH2、NHR1或NR1R2；和
-R1和R2彼此独立地选自烷基、芳基、芳烷基、烷芳基、烷氧基、糖和芳氧基，其可以是直链的、支链的、环状的、多环的、不饱和的、羟基化的、羰基化的、磷酸化的和/或硫化的，所述基团具有1至24个碳原子并且任选地在其主链中具有一个或多个杂原子O、S和/或N。
如通常使用的，在LLAN肽序列中：氨基酸L对应于亮氨酸(Leu)，氨基酸A对应于丙氨酸(Ala)并且氨基酸N对应于天冬酰胺(Asp)。
该肽序列对应于真皮ECM大分子Emilin 1的片段，Emilin 1是一种位于在附近发现弹性蛋白和微纤维的位点水平的糖蛋白。
在N末端，当X＝H时，这意味着末端氨基酸L没有被修饰。在C末端，当Z＝OH时，这意味着末端氨基酸N没有被修饰。当X＝H且Z＝OH时，根据本发明的四肽因此是非衍生形式。四肽在N末端和/或C末端进行衍生化的目的特别是通过增强皮肤渗透来改善肽的生物分散性。这种作用也可以通过肽的载体化，例如通过封装来获得。
下面给出的体外测试的详细描述表明，本发明的四肽有利地对重要的ECM分子表现出活性，从几个ppm起具有活性，并且可以用于改善皮肤及其覆盖物的外观和一般状况，且特别是用于处理和/或预防皮肤及其覆盖物的老化迹象和/或缺陷。
本发明人已经表明，令人惊讶的是根据本发明的四肽可以刺激胶原蛋白I和肌原纤蛋白1的合成。
肌原纤蛋白1是一种由成纤维细胞和平滑肌细胞产生的结缔组织蛋白，有助于形成细胞外微纤维。含有肌原纤蛋白的微纤维与基底膜和相邻的弹性纤维相互作用，并可以通过形成支架来帮助稳定细胞外基质。
本发明人还表明，令人惊讶的是根据本发明的四肽适用于毛发处理，更特别地是刺激毛发生长。
根据本发明的其他优选特征：
-根据本发明的四肽在其N-末端和/或C-末端被修饰；优选地仅在其N-末端被修饰；和/或
-R1和R2是1至24个碳原子的烷基链，优选地3至24个碳原子的亲脂烷基链；和/或
-X是酰基基团CO-R1并且Z选自OH、OMe、OEt和NH2，优选地OH；X优选地选自辛酰基(C8)、癸酰基(C10)、月桂酰基(C12)、肉豆蔻酰基(C14)、棕榈酰基(C16)、硬脂酰基(C18)、生物素酰基、反油酰基、油酰基和硫辛酰基(lipoyl)；更优选地选自月桂酰基(C12)、肉豆蔻酰基(C14)和棕榈酰基(C16)；和/或
-Z是OH并且X选自棕榈酰基(C16)、肉豆蔻酰基(C14)和月桂酰基(C12)；更优选地棕榈酰基(C16)。
本发明中还包括在N或C末端包含特定酸衍生物的四肽，所述特定酸衍生物例如抗坏血酸、视黄酸、肉桂酸、齐墩果酸、透明质酸、烟酸、硫辛酸、没食子酸或泛酸的衍生物。
本发明特别优选的四肽是Pal-LLAN-OH(SEQ ID N°7)。
根据本发明的四肽可以是光学纯的或者由L或D异构体或其混合物组成。那些天然存在的L异构体可以是优选的。
本发明还包括衍生物(对一个或多个氨基酸进行化学官能团的修饰和/或添加，但碳骨架中没有变化)和类似物(对一个或多个氨基酸的化学官能团的修饰和/或者添加，但另外碳骨架有变化)，以及与其他物类如金属离子(如铜、锌、锰、镁等)的复合物。
四肽可以任选地是盐的形式，特别是盐酸盐或乙酸盐。
根据本发明的活性肽序列LLAN也可以形成在该序列任一侧具有额外氨基酸的肽的一部分。
本发明还提供了一种组合物，特别是局部组合物，其包含根据本发明的四肽和生理上可接受的介质。根据生理上可接受的介质和四肽的剂量，该组合物可以构成浓缩的活性成分，旨在以进入用于消费者的最终组合物，或者可以直接构成浓缩程度较低的所述最终组合物。
在根据本发明的组合物中，至少一种四肽可以以更高或更低的浓度存在，这取决于其目的地，相对于组合物的总重量在10-7％至20％的范围内，优选地相对于组合物的总重量，按重量计在10-6％至10％，更优选在10-5％至5％的范围内。
例如，在形成活性成分的组合物中，至少一种四肽将以更高的浓度存在，所述浓度通常在0.001％至1％(10ppm至10,000ppm)的范围内，优选地在0.01％至0.15％(100ppm至1500ppm)的范围内。然后，这种成分通常配制为1％至10％。
除非另有规定，本申请中使用的所有百分比和比率都是相对于总组合物的重量表示的并且所有测量都是在25℃进行的。
根据本发明，“生理上可接受的介质”是指但不限于水溶液或水醇溶液、油包水乳液、水包油乳液、微乳液、水凝胶、无水凝胶、美容液(serum)、囊泡分散体或粉末。
“生理上可接受”是指组合物适用于局部或透皮使用，与哺乳动物，尤其是人类的粘膜、指甲、头皮、毛发、体毛和皮肤接触，可以摄入或注射到皮肤中的组合物，没有毒性、不相容性、不稳定性、过敏反应等的风险。这种“生理上可接受的介质”形成了通常所说的组合物的赋形剂。
根据本发明的四肽可以溶解在亲脂性或亲水性基质中，任选地使用增溶剂，这取决于预期的应用。
根据本发明的处理中的肽可以与其他有效浓度的活性成分组合，这些活性成分可以协同作用或增强作用，以达到本发明所述的预期效果，例如有以下作用的试剂：抗衰老、抗皱纹和细纹、提亮、促色素形成、湿润、保湿、减肥、抗痤疮，抗炎、抗氧化、作用于肤色的光泽、抗糖化、丰盈、重建、抗羰基化、皮肤松弛剂、抗毛发生长、作用于角质层、作用于真皮-表皮连接处、作用于HSP蛋白的产生、作用于紧致度、弹性、肤色、毛发生长(例如睫毛、眉毛)等。
这些活性成分可以从植物材料中获得，例如植物提取物或体外植物培养或发酵的产物。
更具体地，四肽可以与选自以下的化合物中的至少一种组合：维生素B3化合物，化合物如烟酰胺或生育酚，类视黄醇化合物如视黄醇，己脒定，α-硫辛酸，白藜芦醇或DHEA，透明质酸，肽，特别是Ac-YR-十六烷基酯(也称为N-乙酰基-Tyr-Arg-O-十六烷基酯)、Pal-VGVAPG(SEQ ID N°3)、Pal-KTTKS(SEQ ID N°1)、Pal-GHK、Pal-KMO2K、Pal-GQPR(SEQ ID N°2)和Pal-K(P)HG，它们是用于局部美容或皮肤药物组合物的已知活性成分。
更优选地，根据本发明的四肽与肽Ac-YR-十六烷基酯、Pal-GHK和/或Pal-GQPR(SEQ ID N°2)相关联。
可以有利地与根据本发明的四肽组合的其他化合物在下面的详细描述中提到，特别是在盖仑制剂部分提到。
根据本发明的组合物可以应用至面部、身体、颈线、头皮、毛发、睫毛、体毛，以本领域技术人员已知的任何形式或媒介物，特别是以溶液、分散体、乳液、糊状物或粉末的形式，单独地或作为预混合物，或单独地或作为预混物通过载体输送，载体如大胶囊、微胶囊或纳米胶囊，大球、微球或纳米球，脂质体、油质体或乳糜微粒，大颗粒、微颗粒或纳米颗粒，大海绵、微海绵或纳米海绵，微乳液或纳米乳液，或吸附在粉状有机聚合物、滑石、膨润土、孢子或外泌物和其他矿物或有机支持物上。
在美容品中，可以提出应用在例如面部、身体、毛发(包括睫毛、眉毛和体毛)的皮肤护理范围和化妆处理范围内。
一般来说，根据本发明的肽可以以任何形式、以连接的形式、掺入或吸附在大颗粒、微米颗粒和纳米颗粒上，或大胶囊、微胶囊和纳米胶囊上，用于处理纺织品、天然或合成纤维、羊毛和所有旨在与皮肤或毛发接触的材料，并且其可以用于衣物、白天或夜晚内衣、手帕或织物，以便通过这种皮肤或毛发/织物的接触来发挥其美容或治疗(皮肤科)效果，并允许连续的局部递送。
CTFA(“International Cosmetic Ingredient Dictionary&Handbook(国际美容品成分词典和手册)”，由华盛顿特区“The Cosmetic,Toiletry,and FragranceAssociation,Inc.(美容品、洗漱用品和香料协会股份有限公司)”出版)描述了护肤行业常用的多种美容品成分，但不限于这些成分，这些成分适合用作根据本发明的组合物中的附加成分。
其他特别有用的附加护肤活性物质可以在Sederma的商业文献和www.croda.com上找到。
以下销售的活性成分也可以作为实例提及：甜菜碱、甘油、Actimoist Bio2TM(Active organics)、AquaCateenTM(Mibelle AG Cosmetics)、AquafelineTM(Silab)、AquregulKTM(Solabia)、CarcilineTM(Greentech)、CodiavelaneTM(Biotech Marine)、DermafluxTM(Arch Chemicals，Inc)、Hydra'FlowTM(Sochibo)、Hydromoist LTM(Symrise)、RenovHyalTM(Soliance)、SeamossTM(Biotech Marine)、ArgirelineTM(来自Lipotec的乙酰基六肽-3的商品名)、spilanthol或以商品名Gatuline ExpressionTM已知的千日菊(Acmella oleracea)的提取物、名为BoswellinTM的齿叶乳香树(Boswellia serrata)的提取物、Deepaline PVBTM(Seppic)、Syn-AKETM(Pentapharm)、AmelioxTM、BioxiliftTM(Silab)、PhytoCellTecTMArgan(Mibelle)、Papilactyl DTM(Silab)、PreventheliaTM(Lipotec)，或Sederma销售的以下美容品活性成分中的一种或多种：SubleskinTM、VenuceaneTM、Moist24TM、Vegesome Moist 24TM、EssenskinTM、JuvinityTM、RevidratTM、ResistemTM、ChronodynTM、KombuchkaTM、ChromocareTM、CalmosensineTM、Glycokin factor STM、BiobustylTM、IdealiftTM、Ceramide 2TM、Ceramide A2TM、Ceramide HO3TM、LeganceTM、IntenslimTM、ProdiziaTM、BeautifeyeTM、PacifeelTM、ZingerslimTM、MeiritageTM、SenestemTM、SebulessTM、MajestemTM、ApiscalpTM、RubistemTM、CitystemTM、NeonycaTM、NG Unsaponifiable sheabutterTM、MajestemTM、HydronesisTM、PoretectTM、CrystalideTM、AmberstemTM、SynchrolifeTM、FeminageTM、AmeyezingTM、或其混合物。
更优选地，根据本发明的组合物包含至少一种以下活性成分：IdealiftTM(基于肽Ac-YR-十六烷基酯)和/或3000(基于Pal-GHK和Pal-GQPR肽的混合物)，优选地IdealittTM和/>3000。
在可以与根据本发明的肽组合的植物提取物(以经典植物提取物的形式或通过体外方法制备)中，可以更特别地提到常春藤的提取物，特别是英国常春藤(Hedera helix)的提取物，柴胡(Bupleurum chinensis)的提取物，阿尔泰柴胡(Bupleurum falcatum)的提取物，山金车(Arnica montana L)的提取物，迷迭香(Rosmarinus officinalis N)的提取物，金盏花(Calendula officinalis)的提取物，鼠尾草(Salvia officinal L)的提取物，人参(Panax ginseng)的提取物，银杏的提取物，圣约翰草(贯叶连翘(Hyperycum perforatum))的提取物，屠夫扫帚树(假叶树(Ruscus acureatus L))的提取物，欧洲草地甜(旋果蚊草子(Filippendula ulmaria L))的提取物，大花茉莉花茶(Orthosiphop stamincus benth)的提取物，洋蓟(Cynara scolymus)的提取物，藻类(墨角藻(Fucus vesiculosus))的提取物，桦树(Betula alba)的提取物，绿茶的提取物，可乐果(Cola nipida)的提取物，马栗树的提取物，竹子的提取物，积雪草(Centella asiatica)的提取物，帚石南的提取物，岩藻属的提取物，柳树的提取物，鼠耳草属的提取物，七叶菊属的提取物，苍竹属的提取物，金黄洋甘菊(Chrysanthellum indicum)的提取物，杏属(Armeniacea)、Atractylodis platicodon、Sinnomenum、Pharbitidis、千斤拔属(Flemingia)的植物的提取物，鞘蕊花属(Coleus)例如毛喉鞘蕊花(C.Forskohlii)、彩叶草(C.blumei)、毛萼鞘蕊花(C.esquirolii)、五彩苏(C.scutellaroides)、黄鞘蕊花(C.xanthantus)和毛喉鞘蕊花(C.Barbatus)的提取物，例如毛喉鞘蕊花的根的提取物，巴劳草(Ballote)的提取物，Guioa的提取物，骨碎补属(Davallia)的提取物，诃子属(Terminalia)的提取物，玉蕊属(Barringtonia)的提取物，山黄麻属(Trema)的提取物，Antirobia的提取物，Cecropia的提取物，Argania的提取物，薯蓣属(Dioscoreae)例如山药(Dioscorea opposita)或Mexican的提取物，阿米芹(Ammivisnaga)的提取物，豨莶属(Siegesbeckia)特别是豨莶草(Siegesbeckia orientalis)的提取物，杜鹃花科(Ericaceae)的植物提取物特别是越橘提取物(Vacciniumangustifollium)或熊果(Arctostaphylos uva ursi)，芦荟(aloe vera)，含有甾醇的植物(如植物甾醇)，Manjitha(从茜草属(Rubia)植物，特别是茜草(Rubia cordifolia)中提取)和Guggal(从没药属(Commiphora)植物，尤其是穆库没药(Commiphora mukul)中提取)，可乐提取物，甘菊，红三叶草提取物，卡瓦胡椒(Piper methysticum)提取物(来自Sederma的Kava KavaTM)，假马齿苋(Bacopa monieri)提取物(来自Sederma的BacocalmineTM)和海鞭提取物，洋甘草(Glycyrrhiza glabra)的提取物，桑树的提取物，melaleuca(茶树)的提取物，极叉开拉瑞阿(Larrea Divaricata)的提取物，冬凌草(Rabdosia rubescens)的提取物，纤细裸藻(Euglena gracilis)的提取物，黄藤(Fibraurea recisa Hirudinea)的提取物，Chaparral Sorghum的提取物，向日葵提取物，绿花恩南番茄(Enantia chlorantha)的提取物，丰花草属(Spermacocea)的Mitracape的提取物，Buchu barosma的提取物，散沫花(Lawsonia inermis L.)的提取物，曼舞铁线蕨(Adantiumcapillus veneris L.)的提取物，白屈菜(Chelidonium majus)的提取物，丝瓜(Luffa cylindrica)提取物，日本柑橘(Citrus reticulata Blanco var.unshiu)的提取物，茶树(Camelia sinensis)的提取物，白茅(Imperata cylindrica)的提取物，黄花海罂粟(Glaucium Flavum)的提取物，地中海柏木(Cupressus sempervirens)的提取物，多花黄精(Polygonatum multiflorum)的提取物，雪胆块根(Loveyly hemsleya)的提取物，接骨木花(Sambucus nigra)的提取物，棉豆(Phaseolus lunatus)的提取物，百金花属(Centaurium)的提取物，巨藻(Macrocystispyrifera)的提取物，白花蛇舌草(Turnera diffusa)的提取物，知母(Anemarrhenaasphodeloides)的提取物，毛马齿苋(Portulaca pilosa)的提取物，啤酒花(Humuluslupulus)的提取物，阿拉卡比咖啡(Coffea arabica)的提取物，巴拉圭冬青(Ilexparaguariensis)的提取物，或心叶球花(Globularia cordifolia)的提取物，合欢(Albizzia julibrissin)的提取物，Oxydendron arboretum的提取物，红球姜(Zingimberzerumbet smith)的提取物，黄芪(Astragalus membranaceus)的提取物，白术(Atractylodes macrocephalae)的提取物，长叶车前(Plantago lanceolata)的提取物，高山火绒草(Leontopodium alpinum)的提取物，紫茉莉(Mirabilis jalapa)的提取物，欧夏至草(Marrubium vulgare)的提取物，旱芹(Apium graveolens)的提取物，欧夏至草(Marrubium vulgare)的提取物，大叶醉鱼草(Buddleja davidii Franch)的提取物，黄杞(Engelhardia chrysolepis)的提取物，欧丁香(Syringa vulgaris)的提取物或兰花的提取物。
本发明的组合物可以包括其他附加肽，包括但不限于二肽、三肽、四肽、五肽和六肽及其衍生物。根据一个特定的实施方案，组合物中附加肽按重量计的浓度范围为1x10-7％至20％，优选地1x10-6％至10％，优选地1x10-5％至5％。术语“肽”在本文中是指含有10个或更少氨基酸的肽、它们的衍生物、异构体以及与其他物类如金属离子(如铜、锌、锰、镁等)的复合物。术语“肽”是指天然肽和合成肽两者。它还指含有肽并且在自然界中发现和/或可商购的组合物。
用于本文的合适的二肽包括但不限于肌肽(βAH)、YR、VW、NF、DF、KT、KC、CK、KP、KK、TT、PA、PM或PP。
用于本文中的合适的三肽包括但不限于RKR、HGG、GKH、GHK、GGH、GHG、KGH、KHG、KFK、KAvaK、KβAK、KAbuK、KAcaK、KPK、KMOK、KMO2K(MO2是二氧化亚砜甲硫氨酸)、KVK、PPL、PPR、SPR、QPA、LPA、SPA、K(Ac)HG或K(Ac)GH，K(Ac)是具有乙酰化侧链的胺官能团的赖氨酸，如WO2017/216177中所公开的，K(P)HG或K(P)GH，K(P)是其侧链接枝有脯氨酸的赖氨酸，K(Pyr)HG或K(Pyr)GH，K(Pyr)是其侧链接枝有焦谷氨酸的赖氨酸，K(Hyp)HG或K(Hyp)GH，K(Hyp)是其侧链接枝有羟脯氨酸的赖氨酸，如WO2016/07965中所公开。
用作本文中附加肽的合适的四肽包括但不限于RSRK(SEQ ID N°8)、GQPR(SEQ IDN°9)、KTFK(SEQ ID N°10)、KTAK(SEQ ID N°11)、KAYK(SEQ ID N°12)或KFYK(SEQ ID N°13)。
五肽的合适的非限制性实例是KTTKS(SEQ ID N°4)、KTSKS(SEQ ID N°14)和YGGFXaa(SEQ ID N°15)，其中Xaa是Leu或Pro，以及六肽的合适的非限制性实例是GKTTKS(SEQ ID N°16)、VGVAPG(SEQ ID N°5)和HLDIIXaa，其中Xaa是Trp、Phe、Tyr、Tic、7-羟基-Tic或Tpi(SEQ ID N°17)。
根据本发明使用的其他合适的肽可以选自非限制性的列表：肽的亲脂性衍生物，优选地棕榈酰(Pal)衍生物或肉豆蔻酰(Myr)衍生物，以及上述金属络合物(例如三肽HGG或GHK的铜络合物)。优选的二肽包括例如N-棕榈酰-β-Ala-His、N-乙酰基-Tyr-Arg-十六烷基酯(来自Sederma的CalmosensineTM、IdealiftTM)、Pal-RT或Pal-KT(来自Sederma)。优选的三肽衍生物包括例如Pal-GKH和Pal-GHK(来自Sederma)、HGG的铜衍生物(来自Sigma的LaminTM)、Lipospondin(N-反油酰基-KFK)及其保守取代的类似物、N-乙酰基-RKR-NH2(肽CK+)、N-Biot-GHK(来自Sederma)、Pal-KAvaK、Pal-KβAlaK、Pal-KAbuK、Pal-KAcaK或Pal-KMO2K(来自Sederma的)、Pal-KVK(DSM的Syn-CollTM)、Pal-K(P)HG(来自Sederma的Matricyl/>)及其衍生物。
本文还可以提及WO2015181688申请中描述的通式X-Pro*-Pro*-Xaa-Y的抗衰老三肽，其中Xaa选自Leu、Arg、Lys、Ala、Ser和Asp，在N末端，X选自H、-CO-R1和-SO2-R1，并且在C末端，Y选自OH、OR1、NH2、NHR1或NR1R2，R1和R2彼此独立地选自烷基、芳基、芳烷基，烷芳基、烷氧基和芳氧基基团，其可以是直链的、支链的、环状的、多环的、不饱和的、羟基化的、羰基化的、磷酸化的和/或硫化的，所述基团可能在其骨架中具有杂原子，特别是O、S和/或N，以及Pro*对应于脯氨酸、其类似物或衍生物；包括例如Myr-PPL-OH和Myr-PPR-OH。
本文还可以进一步引用WO2014/080376中公开的通式X–(Xaa1)n–Pro*–Xaa2–Y的促色素形成和/或前mec二肽和三肽，其中n＝0、1或2，Xaa1是选自Ala、Val、Met、Leu、Iso、Phe、Pro及其类似物和衍生物的疏水性氨基酸；或是选自Ser、Thr、Tyr、Asp、Glu及其类似物和衍生物的极性氨基酸；并且当n＝2时，两个氨基酸Xaa1相同或不同；Xaa2是选自Ala、Val、Met、Leu、Iso、Phe及其类似物和衍生物的疏水性氨基酸，或是选自Arg、Lys、His及其类似物和衍生物的碱性氨基酸；在N末端的X选自H、-CO-R1和-SO2-R1；在C末端的Y选自OH、OR1、NH2、NHR1或NR1R2；R1和R2彼此独立地选自烷基、芳基、芳烷基、烷芳基、烷氧基和芳氧基基团，其可以是直链的、支链的、环状的、多环的、饱和的、不饱和的、羟基化的、羰基化的、磷酸化的和/或硫化的，所述基团在其骨架中具有或不具有O、S和/或N杂原子，并且Pro*对应于脯氨酸、其类似物或衍生物；包括例如以下肽：Pal-SPR-OH、Pal-PPR-OH、Pal-QPA-OH、Pal-LPAOH、Myr-SPA-OH、Pal-PM-OH、Pal-PA-OH和Pal-PP-OH。
根据本发明用作附加肽的合适的四肽衍生物包括但不限于Pal-GQPR(SEQ ID N°2)(来自Sederma)、Ela-KTFK(SEQ ID N°18)、Ela-KTAK(SEQ ID N°19)、Ela-KAYK(SEQ IDN°20)、Ela-KFYK(SEQ ID N°21)或Pal-KTFK(SEQ ID N°22)。用作本文的附加肽的合适的五肽衍生物包括但不限于Pal-KTTKS(SEQ ID N°1)(可从Sederma以获得)、Pal-KTSKS(SEQ ID N°23)、Pal-YGGFXaa(SEQ ID N°24)，其中Xaa为Leu或Pro，或其混合物。
本文中使用的合适的六肽衍生物包括但不限于Pal-VGVAPG(SEQ ID N°3)、Pal-GKTTKS(SEQ ID N°25)、Pal-HLDIIXaa，其中Xaa为Trp、Phe、Tyr、Tic、7-羟基-Tic或Tpi(SEQID N°26)及其衍生物。还可以提及Pal-GHK和Pal-GQPR(SEQ ID N°2)的混合物(3000，Sederma)。
市售可得的含有三肽或衍生物的优选组合物包括Sederma的Biopeptide-CLTM、MaxilipTM、BiobustylTM、ProcapilTM、或Matrixyl/>四肽的市售可得的组合物优选来源包括RiginTM、EyelissTM、/>Reloaded和其含有50至500ppm的Pal-GQPR(SEQ ID N°2)和赋形剂，它们是由Sederma提出的。
可以提及以下市售肽以及附加活性成分：
-VialoxTM(INCI名称＝五肽-3(包含丙氨酸、精氨酸、异亮氨酸、甘氨酸和脯氨酸的合成肽)、Syn-akeTM(β-Ala-Pro-Dab-NH-Bzl)或Syn-CollTM(Pal-Lys-Val-Lys-OH)，由Pentapharm销售；
-ArgirelineTM(Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2(INCI名称＝乙酰六肽-3)(SEQID N°27)、LeuphasylTM(Tyr-D-Ala-Gly-Phe-Leu)(SEQ ID N°28)、AldenineTM(Gly-His-Lys)、TrylagenTM(INCI名称＝假交替单胞菌(Pseudoalteromonas)发酵提取物、水解小麦蛋白、水解大豆蛋白、三肽-10瓜氨酸(瓜氨酸和三肽-10(由天冬氨酸、异亮氨酸和赖氨酸构成的合成肽)的反应产物)、三肽-1)、EyeserylTM(Ac-β-Ala-His-Ser-His)(SEQ ID N°29)、SerilesineTM(Ser-Ile-Lys-Val-Ala-Val)(SEQ ID N°30)或DecorinylTM(INCI名称：三肽-10瓜氨酸＝瓜氨酸和三肽-10(由天冬氨酸、异亮氨酸和赖氨酸构成的合成肽)的反应产物)，由Lipotec销售；
-CollaxylTM(Gly-Pro-Gln-Gly-Pro-Gln(SEQ ID N°31))或QuintescineTM(Cys-Gly)，由Vincience销售；
-CytokinolTMLS(酪蛋白水解物)，由Les Laboratoires Serobilogiques/Cognis销售；
-KollarenTM(Gly-His-Lys)、IP2000TM(Pal-Val-Tyr-Val)或MelipreneTM(INCI名称＝单氟七肽-1：乙酸和合成肽的反应产物，所述合成肽包含精氨酸、甘氨酸、谷氨酸、组氨酸、正亮氨酸、对氟苯丙氨酸和色氨酸)，由l’lnstitut Européen de BiologieCellulaire销售；
-NeutrazenTM(Pal-His-D-Phe-Arg-NH2)，由Innovations销售；或
-BONT-L-肽TM(INCI名称＝棕榈酰六肽-19：棕榈酸和六肽-19(由天冬酰胺、天冬氨酸、赖氨酸和甲硫氨酸构成的合成肽)的反应产物)、Timp-肽TM(INCI名称＝乙酰六肽-20：通过乙酰化六肽-20(由丙氨酸、甘氨酸、赖氨酸、缬氨酸和脯氨酸构成的合成肽)获得的反应产物)或ECM ModulineTM(INCI名称＝棕榈酰三肽-28：棕榈酸和三肽-28(由精氨酸、赖氨酸和苯丙氨酸构成的合成肽)的反应产物)，由lnfinitec Activos销售。
因此，本发明提供了根据本发明的四肽或包含它的组合物(如上文所定义)用于非治疗性美容处理以改善皮肤和/或其附件的一般状况并处理缺陷的用途。处理包括将有效量的根据本发明的四肽应用于有此需要的皮肤和/或其附件。
根据本发明，处理优选地是局部处理。
根据本发明的四肽更特别地适用于根据本发明的抗衰老处理(作为预防性的和/或治疗性的)，特别是处理：
-抗皱纹和细纹；和/或
-改善皮肤的机械性能：紧致度、色调、弹性和/或柔韧性；和/或
-增加皮肤的密度和体积(丰盈、饱满和/或重建效果)；和/或
-以对抗妊娠纹；和/或
-以对抗皮肤下垂；和/或
-以改善肤色的均匀性和光泽。
根据本发明的四肽可以考虑其他应用，例如保湿、减肥、解毒、抗糖化、抗自由基、紧肤、抗疲劳、抗浮肿和/或黑眼圈、舒缓/镇静、作用于毛发生长、作用于色素沉着、作用于头皮等，作为预防性或治疗性处理。
下面详细描述的体外测试特别显示，根据本发明的肽可以刺激毛发生长。
因此，根据本发明的四肽进一步更特别地适用于毛发生长刺激处理。
本发明提供了一种用于改善皮肤及其覆盖物的外观和一般状况的美容、非治疗性局部处理方法，包括将有效量的根据本发明的肽或包含所述肽的根据本发明的组合物局部应用于有此需要的受试者的皮肤，所述肽如上文所定义。
“非治疗性美容处理”是指旨在用于处于健康状态(而不是病理状态)的皮肤及其覆盖物的处理，目的是美化皮肤或避免病症(作为预防措施)，特别是审美或感官病症。
“局部处理”或“局部使用”是指旨在作用于应用部位的应用，所述应用部位为：皮肤、粘膜、覆盖物。
根据本发明的肽或组合物可以局部应用至靶向区域。
“有效”量取决于各种因素，如年龄、使用者的皮肤状态、病症的严重程度和施用方式。有效量是指足以达到所需效果(特别是或多或少明显的效果)的无毒量。
例如，对于面部美容处理，欧洲美容品指令(European Cosmetics Directive)设定了2.72mg/cm2/天/人的面霜标准应用量和0.5mg/cm2/天/人的身体乳液的标准应用量。
根据其他特征，根据本发明的美容处理方法可以与一种或多种针对皮肤的其他处理方法相关联，所述其他处理方法例如光疗、加热、振动、电穿孔处理、微针贴片或芳香疗法。
根据本发明，可以提出具有旨在用于实施上述方法的几个隔室或试剂盒的装置，并且其可以包括例如但不限于在第一隔室中包含根据本发明的四肽的组合物和在第二隔室中的赋形剂和/或附加活性剂，包含在所述第一和第二隔室中的组合物在本文中被认为是用于同时、分开或随时间分散使用的组合用组合物，特别是在上述定义的一种处理中使用。
根据本发明的处理方法更特别适合于减缓真皮细胞外基质的分子的降解。
根据另一个目的，本发明提供了根据本发明的四肽作为活性成分在制备美容品组合物中的用途，所述美容品组合物用于改善皮肤和/或其附件的一般状况并处理其缺陷。
发明详述
根据以下实施方案和体外测试的描述将更好地理解本发明。
A-合成根据本发明的四肽的实施例：Pal-LLAN-OH(SEQ ID N°7)
Pal-LLAN-OH是通过肽合成制备的。N-保护的天冬酰胺通过其末端酸官能团附着在树脂上。胺官能团被去保护，然后天冬酰胺-树脂与丙氨酸衍生物在偶联剂(例如DCC(二氯己基碳二亚胺)/NHS(N-羟基琥珀酰亚胺)或HBTU(2-(1H-苯并三唑)-1-基)-1,1,3,3-四甲基脲基六氟磷酸酯)/HOBT(1-羟基-苯并噻唑)的存在下反应，然后重复相同的去保护和偶联操作以添加第一亮氨酸、第二亮氨酸和棕榈酸。然后在酸性介质中将肽从树脂上切割下来，并在沉淀、洗涤和干燥后，获得固体形式的产物棕榈酰基-亮氨酰基-亮氨酰基-丙氨酰基-天冬酰胺。
根据本发明的四肽也可以通过能够至少部分生产它的微生物以进行生物技术制备。
B-制备根据本发明的组合物的实施例，所述组合物包含实施例A的四肽Pal-LLAN-OH
起始材料：
-根据上述合成方法合成的纯肽。
-赋形剂：脂肪酯的混合物，选择以形成油性基质，例如旨在形成无水组合物，用于随后的无水美容品组合物的配制。
方案：将选定量的两种肽中的一种与赋形剂混合，并置于温和搅拌和加热下，直到溶解并完全澄清。
在一个特定的实施例中，将1200ppm的本发明的肽Pal-LLAN-OH之一与赋形剂混合以形成用于以下盖仑制剂部分D)中的活性成分。
C-体外评估
根据本发明的四肽表现出如下所述的显著效果。对根据上述A)制备并溶解在赋形剂中的四肽进行了体外测试，并显示出如下所示的活性。
1-MEC蛋白的刺激
1.1-ELISA测定法
方案
使培养中的正常人成纤维细胞(NHF)与待测试产品或其赋形剂(阴性对照)接触72h。在接触结束时，去除培养物上清液，并通过ELISA测定法估计真皮大分子的合成。通过Hoechst测定法对细胞活力进行估计，以对所获得的数据进行加权。
胶原蛋白I通过PIP测定法(前胶原蛋白I的羧基末端前肽)进行评估，胶原蛋白I是前胶原蛋白在排出成纤维细胞外时被酶促降解产生的肽片段(因此在进行测定法的培养基中)。
结果
表1
1.2-免疫荧光测定法
方案
将正常人成纤维细胞(NHF)在含有血清的成纤维细胞生长培养基中培养至少24小时。一旦达到汇合，接种细胞，并加入在培养基中稀释的活性物质和相应的对照。在五天孵育期结束时，除去上清液，用PBS洗涤细胞并固定。然后将细胞与在封闭缓冲液中以1∶200的浓度稀释的一级肌原纤蛋白1单克隆抗体(11C1.3)(Thermo Fisher)一起孵育。孵育细胞。去除一级抗体，并用PBS洗涤细胞。加入二级抗体(在封闭缓冲液中1∶1000的稀释度)，然后去除，并用PBS洗涤细胞。使用荧光显微镜观察细胞形成的肌原纤蛋白1。使用将数值分配给覆盖密度的图像处理软件来分析所获得的图像。
结果
表2：
| Pal-LLAN-OH(8ppm) | |
| 肌原纤蛋白1(显著性) | +108％(p<0.05) |
所有这些结果显示了根据本发明的四肽对美容处理的好处特别基于以几个ppm的浓度对以下的刺激：ECM的成纤维细胞的胶原蛋白I和肌原纤蛋白1的合成。
2-刺激毛发生长
2.1-细胞培养物(毛囊真皮乳头细胞(HFDPC)和外根鞘角质形成细胞(ORSK))的增殖研究
方案
将细胞接种在适应的培养基中，孵育24h。然后去除培养基，换成测试培养基，并孵育细胞。然后将细胞与肽(在DMSO中以不同浓度稀释)和EdU(乙炔基脱氧尿苷)接触，EdU是一种胸腺嘧啶核苷类似物核苷，其被掺入新合成的增殖细胞中。停止培养，并使用Edu检测试剂盒对细胞进行标记。
结果
表3：HFDPC
| Pal-LLAN-OH | 细胞增殖变化％vs.对照溶剂(DMSO) | 显著性vs.对照 |
| 5ppm | +13.7％ | p<0,01 |
| 10ppm | +22.15％ | p<0,01 |
这些结果表明，在与根据本发明的肽接触后本发明的肽诱导HFDPC的显著增殖。
表4：ORSK
| Pal-LLAN-OH | 细胞增殖变化％vs.对照溶剂(DMSO) | 显著性vs.对照 |
| 5ppm | +55％ | p<0,01 |
这些结果表明，在与根据本发明的肽接触后本发明的肽诱导ORSK的显著增殖。
2.2-从毛囊球的毛发生长
方案
毛发制备：
通过显微切割从手术后的头皮外植体中分离出整个毛囊(包括漏斗部、上鞘、凸起、下鞘和毛球)。在第一天(D0)，将毛发单独放置在孔中，并在37℃，在富含5％ CO2的湿润环境中，在适应的培养基中保持活力。
用于处理的肽产物的制备：
在含有0.1％ DMSO的培养基中制备10ppm和5ppm的肽溶液。
处理：
在D0、D3、D5和D7，将肽产物掺入培养基中。每次处理都对培养基进行完全更新。对照例除了更新培养基外，不接受任何处理。
样本：
在D0天，移除毛发并在-80℃冷冻保存。在D10，以相同的方式采集和处理每例的毛发。
增长测量：
在D0拍摄分离毛发的照片，以使用图像分析软件测量从毛球到发干末端的毛发。在D3、D5、D7和D10重复进行拍摄和长度测量。每根毛发的生长都是单独监测的。
结果
在研究过程中，毛发生长。为了估计肽的效果，每次比较肽和溶剂对照之间的平均毛发长度(见下表5)。
表5：每次与溶剂对照(0.1％ DMSO)相比的生长变化
| Pal-LLAN-OH | D3 | D5 | D7 | D10 |
| 5ppm | +21％(nsd) | +26％* | +32％** | +30％** |
| 10ppm | +16％(nsd) | +28％* | +37％** | +38％** |
nsd：非显著的数据；*p<0.05；**p<0.01
这些结果显示了从D5到D10(研究停止时间)对毛发生长的显著刺激。
D-盖仑制剂(Galenics)
下文描述了不同的制剂。支持和/或补充根据本发明的活性成分的活性的其他美容品活性物质可以根据其疏水性或亲水性加入在适当的相中。这些成分可以根据其作用、应用位置(身体、面部、颈部、胸部、手、毛发、睫毛、眉毛、体毛等)、所需最终效果和目标消费者而分为任何类别，例如抗氧化剂、保湿、滋养、保护、平滑、重塑、丰盈(填脂)、作用于肤色光泽、处理斑点、遮瑕膏、抗糖化、减肥、舒缓、肌肉放松、抗发红、抗妊娠纹等。在上文的描述中提到了实例。
下述配方包括基于如上文B点所述的根据本发明四肽的活性成分，包含1200ppm的四肽。配方还可以含有这两种根据本发明的四肽的混合物，所述混合物由以相等比例或不以相等比例包含它们的活性成分配制而成。这些配方是作为指南给出的，并且可以含有更高百分比的根据本发明的活性成分。
1)面霜形式，例如面部的抗衰老日霜或晚霜
表6：
附加活性成分的实例：
补充活性：
1-一种作用于皮肤弹性性能的成分，例如：
IDEALIFTTM，由Sederma销售，包含N-乙酰基-酪氨酰基-精氨酰基-O-十六烷基酯脂肽，通过弹性蛋白刺激对抗面部松弛和改善重力抗性。
BPELTM，由Sederma销售，包含Pal-VGVAPG(SEQ ID N°3)肽。
2-一种更具体地作用于表皮的活性成分，例如：
CRYSTALIDETM，由Sederma销售，包含Pal-KTFK(SEQ ID N°22)肽，由于油-蜡-表面活性剂和水微乳化(其中肽被溶剂化)而在表皮中进行载体化，通过调节表观遗传和炎症现象以及通过协调皮肤成熟过程在表皮中发挥生物和谐作用。
3-保湿/平滑成分，例如：
OPTIMYALTM，由Sederma销售，含有乙酰化葡萄糖醛酸的低聚糖，其结构类似于透明质酸的片段。
4-一种皮脂调节成分，例如：
SEBULESSTM，由Sederma销售，含有通过体外植物细胞培养产生的欧丁香(Syringavulgaris)提取物，它是一种净化皮脂的调节因子，可以滋润和焕新肤色，并模糊瑕疵。
5-一种作用于蓝光有害影响的成分，例如：
SYNCHROLIFETM，由Sederma销售，包含Pal-GQPR肽(SEQ ID N°2)、白杨素和迷迭香提取物；重新平衡昼夜节律周期的关键分子(视蛋白5、周期蛋白2、褪黑激素)的产生，并确保增强的修复代谢(能量、抗氧化、抗炎和皮肤基质修复)。
增强活性：作用于ECM大分子合成的成分，例如：MATRIXYLTM(基于Pal-KTTKS(SEQID N°1)肽，MATRIXYL 3000TM(基于Pal-GQPR(SEQ ID N°2)和Pal-GHK肽的混合物)，MATRIXYL synthe'6TM(基于KMO2K肽)和/或MATRIXYL MorphomicsTM(基于Pal-K(P)HG肽)，它们是由Sederma销售的。
PORETECTTM，由Sederma销售，包括在cylolinopeptide和洋川芎内酯(senkyunolide)中滴定的亚麻和芹菜籽提取物的组合，为皮肤带来紧致度、色调和密度，从而增强随着年龄增长而下垂的皮肤毛孔的维持结构。
FEMINAGETM，由Sederma销售，包含在astilbin(一种糖基化类黄酮)中滴定的黄杞(Engelhardia chrysolepis)提取物，为皮肤提供弹性和紧致特性，尤其是在绝经后妇女中。
2)水性温和美容液形式
表7：
补充活性的附加活性成分的实例：
1-一种抗衰老成分，例如：
SENESTEMTM，由Sederma销售，包含通过体外细胞培养获得的长叶车前(Plantagolanceolata)植物细胞，改善皮肤的粘弹性性能并淡化衰老色素斑。
2-一种抗氧化剂成分，例如：
MAJESTEMTM，由Sederma销售，基于在绒花酸(leontopodic acid)中滴定的高山火绒草(Leontopodium alpinum)植物细胞，通过体外细胞培养获得，中和氧化应激(污染、UVB辐射)并恢复皮肤紧绷。
3)凝胶形式
表8：
补充活性的附加活性成分的实例：
1-一种抗污染成分，例如：
CITYSTEMTM，由Sederma销售，基于具有高连翘酯苷B浓度的欧夏至草(Marrubiumvulgare)植物细胞，通过体外植物细胞培养产生，用于对抗污染攻击，使皮肤柔软光滑，改善皮肤纹理，减少黑头可见性，使皮肤有光泽并纯净。
2-用于敏感皮肤的镇静成分，例如：
PACIFELTM，由Sederma销售，含有紫茉莉(Mirabilis Jalapa)植物提取物。
3-保湿成分，例如：
AQUALANCETM，由Sederma销售，一种由homarin和赤藓糖醇组成的渗透保护性保湿霜。
4)凝胶形式以制作喷雾面膜
表9：
/>
补充活性的附加活性成分的实例：
1-一种作用于肤色光泽的成分，例如：
EVERMATM，由Sederma销售，包含富含原小檗碱(protobberberin)和齐墩果酸的绿花恩南蕃茄(Enantia chlorantha)提取物的组合，减少毛孔大小和明显性，改善易长粉刺的皮肤纹理。
2-一种具有复原特性的成分，例如：
FruitliquidTMKumquatTM，由Crodarom销售。
5)面霜形式，用作化妆基底
表10：
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补充活性的附加活性成分的实例：
1-一种用于处理黑眼圈和眼睛轮廓的成分，例如：
HALOXYLTM，由Sederma销售，这是两种细胞外基质活化素Pal-GHK和Pal-GQPR(SEQID N°2)与N-羟基琥珀酰亚胺和类黄酮、白杨素的结合。
EYELISTM，由Sederma销售，组合三种组分：甲基查尔酮橙皮苷、缬氨酰基-色氨酸肽(VW)和Pal-GQPR(SEQ ID N°2)脂肽。
PRODIZIATM,由Sederma销售，含有合欢(Albizia julibrissin)植物提取物，通过修复和保护皮肤免受糖基化引起的损伤，有助于减少可见的疲劳：黑眼圈、眼袋、暗淡的肤色和憔悴的特征。
2-包含肽的抗皱纹/抗衰老成分，例如：MATRIXYL 3000TMMATRIXYL synthe'6TM和/或MATRIXYL MorphomicsTM，由Sederma销售。
3-一种作用于皮肤光泽的成分，例如AmberstemTM，由Sederma销售，它修饰橄榄康乃馨皮肤(olive carnation skin)，来源于大叶醉鱼草(Buddleja davidii)叶(蝴蝶树)的细胞培养物，通过减少炎症性色素沉着过多、面色暗淡和发红，同时增强皮肤屏障和水合作用，从而作用于皮肤光泽。
序列表
<110> 赛德玛公司（SEDERMA）
<120> 美容四肽、组合物及用途
<130> PEPT JEU 3 PCT
<150> FR2011745
<151> 2020-11-17
<160> 31
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<400> 1
Lys Thr Thr Lys Ser
1 5
<210> 2
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<400> 2
Gly Gln Pro Arg
1
<210> 3
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<400> 3
Val Gly Val Ala Pro Gly
1 5
<210> 4
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 4
Lys Thr Thr Lys Ser
1 5
<210> 5
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 5
Val Gly Val Ala Pro Gly
1 5
<210> 6
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 氨基酸未被修饰或通过酰化-CO-R1或-SO2-R1或通过生物素酰基被修饰，
R1=1至24C，烷基、芳基、芳烷基、烷芳基、烷氧基、糖或芳氧基
<220>
<221> MOD_RES
<222> (4)..(4)
<223> 氨基酸未被修饰或在OR1, NH2, NHR1或NR1R2中被修饰，
R1和R2 =1至24C，烷基、芳基、芳烷基、烷芳基、
烷氧基、糖或芳氧基，R1和R2独立选择
<400> 6
Leu Leu Ala Asn
1
<210> 7
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<400> 7
Leu Leu Ala Asn
1
<210> 8
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 8
Arg Ser Arg Lys
1
<210> 9
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 9
Gly Gln Pro Arg
1
<210> 10
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 10
Lys Thr Phe Lys
1
<210> 11
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 11
Lys Thr Ala Lys
1
<210> 12
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 12
Lys Ala Tyr Lys
1
<210> 13
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 13
Lys Phe Tyr Lys
1
<210> 14
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 14
Lys Thr Ser Lys Ser
1 5
<210> 15
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa是脯氨酸或亮氨酸
<400> 15
Tyr Gly Gly Phe Xaa
1 5
<210> 16
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 16
Gly Lys Thr Thr Lys Ser
1 5
<210> 17
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa是Trp, Phe, Tyr, Tic, 7-羟基-Tic或Tpi
<400> 17
His Leu Asp Ile Ile Xaa
1 5
<210> 18
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过反油酰基链酰化
<400> 18
Lys Thr Phe Lys
1
<210> 19
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过反油酰基链酰化
<400> 19
Lys Thr Ala Lys
1
<210> 20
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过反油酰基链酰化
<400> 20
Lys Ala Tyr Lys
1
<210> 21
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过反油酰基链酰化
<400> 21
Lys Phe Tyr Lys
1
<210> 22
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<400> 22
Lys Thr Phe Lys
1
<210> 23
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<400> 23
Lys Thr Ser Lys Ser
1 5
<210> 24
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa是脯氨酸P或亮氨酸L
<400> 24
Tyr Gly Gly Phe Xaa
1 5
<210> 25
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<400> 25
Gly Lys Thr Thr Lys Ser
1 5
<210> 26
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端通过棕榈酰基链酰胺化
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa是Trp, Phe, Tyr, Tic, 7-羟基-Tic或Tpi
<400> 26
His Leu Asp Ile Ile Xaa
1 5
<210> 27
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 在N末端乙酰化
<400> 27
Glu Glu Met Gln Arg Arg
1 5
<210> 28
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 28
Tyr Ala Gly Phe Leu
1 5
<210> 29
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 29
Ala His Ser His
1
<210> 30
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 30
Ser Ile Lys Val Ala Val
1 5
<210> 31
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 31
Gly Pro Gln Gly Pro Gln
1 5
Claims (17)
1.式1的四肽：
X-LLAN-Z(SEQ ID N°6和SEQ ID N°7)
其中：
-在N末端的X选自H、-CO-R1、-SO2-R1或生物素酰基基团；
-在C末端的Z选自OH、OR1、NH2、NHR1或NR1R2；和
-R1和R2彼此独立地选自烷基、芳基、芳烷基、烷芳基、烷氧基、糖和芳氧基基团，其可以是直链的、支链的、环状的、多环的、不饱和的、羟基化的、羰基化的、磷酸化的和/或硫化的，所述基团具有1至24个碳原子并且任选地在其主链中具有一个或多个杂原子O、S和/或N。
2.根据权利要求1所述的四肽，其中所述基团包含3至24个碳原子。
3.根据权利要求1或2所述的四肽，其中X是酰基基团-CO-R1并且在C末端的Z是选自OH、OMe、OEt和NH2的基团。
4.根据权利要求1-3中任一项所述的四肽，其中酰基基团CO-R1选自辛酰基(C8)、癸酰基(C10)、月桂酰基(C12)、肉豆蔻酰基(C14)、棕榈酰基(C16)、硬脂酰基(C18)、生物素酰基、反油酰基、油酰基和硫辛酰基。
5.根据权利要求1-4中任一项所述的四肽，其中Z是OH。
6.根据权利要求5所述的四肽，其对应于Pal-LLAN-OH(SEQ ID N°7)。
7.美容品组合物，其包含至少一种根据权利要求1-6中任一项所述的四肽和生理上可接受的介质。
8.根据权利要求7所述的组合物，其中四肽的量相对于组合物的总重量为10-7％至20％。
9.根据权利要求7或8所述的组合物，其包含至少一种附加活性成分，所述活性成分选自维生素B3、烟酰胺、生育酚、类视黄醇化合物、己脒定、α-硫辛酸、白藜芦醇、DHEA、透明质酸和一种或多种美容品肽的化合物。
10.根据权利要求7-9中任一项所述的组合物，其包含Pal-GHK和Pal-GQPR的混合物，和/或肽Ac-YR-十六烷基酯。
11.根据权利要求7-10中任一项所述的组合物，其构成用于配制用于消费者的最终组合物的活性成分。
12.至少一种根据权利要求1-6中任一项所述的四肽或根据权利要求7-11中任一项所述的组合物用于非治疗性美容处理以改善皮肤和/或其附件的一般状况并处理其缺陷的用途。
13.根据权利要求12所述的用途，用于局部处理。
14.根据权利要求12或13所述的用途，用于抗衰老处理。
15.根据权利要求12-14中任一项所述的用途，用于处理：
-抗皱纹和细纹；和/或
-改善皮肤的机械性能：紧致度、色调、弹性和/或柔韧性；和/或
-增加皮肤的密度和体积(丰盈、饱满和/或重建效果)；和/或
-以对抗妊娠纹；和/或
-以对抗皮肤下垂；和/或
-以改善肤色的均匀性和光泽。
16.根据权利要求12或13所述的用途，用于毛发处理。
17.根据权利要求16所述的用途，用于刺激毛发生长。
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| FRFR2011745 | 2020-11-17 | ||
| FR2011745A FR3116275B1 (fr) | 2020-11-17 | 2020-11-17 | Tétrapeptide, composition le comprenant et son utilisation cosmétique |
| PCT/EP2021/081729 WO2022106366A1 (en) | 2020-11-17 | 2021-11-15 | Cosmetic tetrapeptide, composition and use |
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| EP (1) | EP4247834A1 (zh) |
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| EP2470159A1 (en) * | 2009-08-28 | 2012-07-04 | Mary Kay, Inc. | Skin care formulations |
| FR2998570B1 (fr) | 2012-11-26 | 2016-12-02 | Sederma Sa | Peptides, compositions les comprenant et utilisations notamment cosmetiques propigmentantes |
| KR101648477B1 (ko) * | 2014-03-25 | 2016-08-16 | 김영수 | 다크서클 개선 및 예방용 화장료 조성물 |
| FR3021319B1 (fr) | 2014-05-22 | 2018-08-31 | Sederma | Peptides, compositions les comprenant et utilisations notamment cosmetiques |
| FR3029782B1 (fr) | 2014-12-16 | 2019-06-07 | Sederma | Composes peptidiques, compositions les comprenant et utilisations notamment cosmetiques |
| FR3052453B1 (fr) | 2016-06-14 | 2018-05-18 | Sederma | Peptide, composition le comprenant et utilisations notamment cosmetiques |
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- 2021-11-15 US US18/035,855 patent/US20240010677A1/en active Pending
- 2021-11-15 WO PCT/EP2021/081729 patent/WO2022106366A1/en active Application Filing
- 2021-11-15 CN CN202180077352.5A patent/CN116615178A/zh active Pending
- 2021-11-15 KR KR1020237020308A patent/KR20230110309A/ko unknown
- 2021-11-15 EP EP21806754.4A patent/EP4247834A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022106366A1 (en) | 2022-05-27 |
| KR20230110309A (ko) | 2023-07-21 |
| EP4247834A1 (en) | 2023-09-27 |
| US20240010677A1 (en) | 2024-01-11 |
| FR3116275B1 (fr) | 2022-09-30 |
| FR3116275A1 (fr) | 2022-05-20 |
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